U.S. Pat. Nos. 4,571,396 and 4,861,779 disclose quinolone antibacterials which are synthesized using 4,5-difluoro-2-chlorobenzoic acid. 4,5-Difluoroanthranilic acid is a starting material for producing the 4,5-difluoro-2-chlorobenzoic acid used in the synthesis of these quinolones. These quinolones are useful in the treatment of bacterial infections of broad spectrum, particularly gram positive bacterial strains.
Synthesis of 4,5-difuoroanthranilic acid has been shown by G. McGraw, et al., J. Chem. and Engineering Data, 13,587 (1968) by nitrating 3,4-difluorobenzoic acid with a mixture of nitric and sulfuric acids to obtain 2-nitro-4,5-difluorobenzoic acid, the latter being reduced to obtain the desired compound. The 3,4-difluorobenzoic acid starting material, however, is expensive and difficult to obtain.
U.S. Pat. No. 4,833,270 also relates to the synthesis of 4,5-difluoroanthranilic acid by, first, reacting 3,4-difluoroaniline with hydroxylamine hydrochloride in the presence of chloral. The resulting intermediate is then cyclyzed using sulfuric acid to form 5,6-difluoroisatin. The 4,5-difluoroanthranilic acid is produced by oxidation of the aforementioned isatin with hydrogen peroxide. As before, however, 3,4-difluoroaniline is expensive and difficult to obtain.
U.S. Pat. Nos. 4,374,266 and 4,374,267 show a multi-step conversion process of 4,5-dichlorophthalic anhydride to 4,5-difluoroanthranilic acid. However, the processes are complex and involves the use of multiple reaction vessels.